US20180092874A1 - Identification and use of very long chain dicarboxylic acids for disease diagnosis, chemoprevention, and treatment - Google Patents
Identification and use of very long chain dicarboxylic acids for disease diagnosis, chemoprevention, and treatment Download PDFInfo
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- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57419—Specifically defined cancers of colon
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
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- G—PHYSICS
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- G01N2800/00—Detection or diagnosis of diseases
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- G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7057—(Intracellular) signaling and trafficking pathways
- G01N2800/7066—Metabolic pathways
- G01N2800/7085—Lipogenesis or lipolysis, e.g. fatty acid metabolism
Definitions
- VLDCA very long chain dicarboxylic acids
- VLDCAs very long chain dicarboxylic acids
- the identified VLCDAs are endogenous anti-inflammatory and anti-proliferative lipids specific to humans.
- Cancer is a type of disease in which abnormal cells begin to divide without control and which can potentially invade other tissues. Cancer cells may spread to various parts of a patient's body through the patient's blood and/or lymph system. There are many types of cancers, of which colorectal cancer has one of the highest mortality rates. However, although there currently exists several early detection screening programs, such as colonoscopy, which have proven effective at detecting colorectal cancer, many people are reluctant to undergo such procedures due to cost and perceived invasiveness. As a result, several minimally-invasive serum-based tests have been developed that identify people who are at a higher risk of developing certain types of cancers, including kidney and colorectal cancer.
- lipidomics analysis involves non-targeted lipidomics analysis of serum from patients who have been diagnosed with colorectal cancer or pancreatic cancer.
- the lipid extracts within the serum are monitored to determine whether a number of masses between 444 and 555 atomic mass units (amu) decrease over a period of time.
- these lipids have been previously misassigned as vitamin E metabolites, and subsequently, as very-long chain hydroxylated polyunsaturated fatty acids, with 1 carboxy function, 2 to 6 double bonds, and 2 to 4 hydroxy substitutions.
- none of these conjectured lipid candidates have been synthesized as analytical standards to validate the structural assumptions and improve the reliability of clinical assays for these biomarkers.
- metabolic markers which may be used as early stage risk indicators in a method for detecting and diagnosing certain types of cancer, including, but not limited to, kidney and colorectal cancer.
- VLCDCAs very-long chain dicarboxylic acids
- VLCDCA 28:4n6 One particular very-long chain dicarboxylic acid (VLCDCA) with 28 carbons and 4 double bonds has potential as a diagnostic marker and as a supplement to provide protection against cancer development.
- This VLCDCA (hereinafter identified as VLCDCA 28:4n6) has formula (I) but does not exclude other variants for localization of the double bonds:
- aspects and advantages of the present general inventive concept may be achieved by providing a method for validation of VLCDCA 28:4 as a dicarboxylic acid which may, in some embodiments, include sequential derivatization of 1 carboxylic group with [2H4]taurine and methylation of the second carboxylic group with trimethylsilyl diazomethane. Reactions may also be monitored by inclusion of the internal standard [2H28]VLCDCA 26:0.
- aspects and advantages of the present general inventive concept may be achieved by providing a method for diagnosing a subjects risk for having colorectal cancer which includes obtaining a blood sample of the subject, isolating serum or EDTA plasma from the blood sample, analyzing the serum or EDTA plasma to determine plasma levels of very long chain dicarboxylic acid (VLCDCA 28:4), comparing the determined plasmas levels of VLCDCA 28:4 of the subject with a predetermined range of plasma levels of VLCDCA 28:4 of diagnosed subjects having colorectal cancer, and determining the subject's risk of having colorectal cancer when the determined plasma levels of VLCDCA 28:4 within the blood sample is within the predetermined range of plasma levels of VLCDCA 28:4.
- VLCDCA 28:4 very long chain dicarboxylic acid
- the foregoing and/or other aspects and advantages of the present general inventive concept may be achieved by providing a method for diagnosing a subjects risk for having colorectal cancer, the method encompassing obtaining a blood sample of the subject; isolating serum or EDTA plasma from the blood sample; analyzing the serum or EDTA plasma to determine plasma levels of VLCDCA 28:4; comparing the determined plasmas levels of VLCDCA 28:4 of the subject with a predetermined range of plasma levels of VLCDCA 28:4 of diagnosed subjects having colorectal cancer; and determining the subject has colorectal cancer when the determined plasma levels of VLCDCA 28:4 within the blood sample is within the predetermined range of plasma levels of VLCDCA 28:4.
- the foregoing and/or other aspects and advantages of the present general inventive concept may be achieved by providing a method of treating a subject having colorectal cancer, the method including administering to the subject a sufficient amount to treat colorectal cancer a very-long chain dicarboxylic acid.
- the very-long chain dicarboxylic acid includes a straight chain group that is a C28-36 aliphatic group.
- the very-long chain dicarboxylic acid includes a straight chain group with between one and four double bonds.
- the very-long chain dicarboxylic acid includes epoxide or hydroxy functional groups.
- the very-long chain dicarboxylic acid is a compound (VLCFA 28:4) of formula (I):
- the foregoing and/or other aspects and advantages of the present general inventive concept may be achieved by providing a method of validating a dicarboxylic acid 28:4 structure, the method encompassing obtaining a blood sample of a subject; isolating serum or EDTA plasma from the blood sample; storing the serum or EDTA plasma in a low temperature environment; mixing about 1 milliliter (mL) of methanol comprising 1 nanomole of [ 2 H 28 ] dicarboxylic acid 16:0 to a sample containing about 100 microliters of serum or EDTA plasma; mixing about 1 mL of distilled water and about 2 ml of tert-butyl methylether with the sample; separating an organic layer from the sample; drying the upper organic layer; dissoluting the dried upper organic layer in a mixture of isopropanol, methanol, and chloroform and ammonium acetate; performing mass spectrometry on the dissolution; and quantiating anions of dicarboxylic acid
- the blood sample of the subject is obtained by venipuncture.
- the low temperature environment includes a refrigerator and a freezer.
- the organic layer is separated from the sample using centrifugal force of about 3000 times gravity.
- the mixture of isopropanol, methanol, and chloroform is at a ratio of 4:2:1.
- the mixture includes about 15 millimolar (mM) of the ammonium acetate.
- the mass spectrometry is performed via direct infusion.
- the foregoing and/or other aspects and advantages of the present general inventive concept may be achieved by supplying a method of providing a chemopreventive agent to a subject having low circulating levels of VLCDAs, the method including: administering to the subject a sufficient amount to act as a chemopreventive agent a compound of formula (I), a prodrug of (I), or an analog of (I):
- a method of validating a dicarboxylic acid 28:4 structure which includes obtaining a blood sample of a subject, isolating serum or EDTA plasma from the blood sample, storing the serum or EDTA plasma in a low temperature environment, mixing about 1 milliliter (mL) of methanol comprising 1 nanomole of [ 2 H 28 ] dicarboxylic acid 16:0 to a sample containing about 100 microliters of serum or EDTA plasma, mixing about 1 mL of distilled water and about 2 ml of tert-butyl methylether with the sample, separating an organic layer from the sample, drying the upper organic layer, dissoluting the dried upper organic layer in a mixture of isopropanol, methanol, and chloroform and ammonium acetate, performing mass spectrometry on the dissolution; and quantiating anions of dicarbox
- the blood sample of the subject may be obtained by venipuncture.
- the low temperature environment may include a refrigerator and/or a freezer.
- the organic layer may be separated from the sample by using a centrifugal force of about 3000 times gravity.
- the mixture of isopropanol, methanol, and chloroform may be at a ratio of 4:2:1.
- the mixture may include about 15 millimolar (mM) of ammonium acetate.
- the mass spectrometry may be performed via direct infusion.
- VLCDCA 28:4 is present in all human biofluids examined (plasma, synovial fluid, pleural fluid, cerebrospinal fluid, and umbilical cord plasma). VLCDCA 28:4 was not detectable in the plasma of dogs, cows, horses, or the non-human primates cynonologous or rhesus macaque. In contrast, VLCDCA 28:4 levels were detected in the plasma of chimpanzees, the closest living human relative of the non-human primates.
- FIGS. 1A and 1B are tables illustrating a listing of VLCDCAs extracted from human blood plasma. The parent masses and masses of the derivatized (carboxy and hydroxyl functional groups) molecules are listed;
- FIG. 2A presents the molecular anion of the parent molecule VLCDCA 28:4 having a spectrum molecular anion of 445.332 amu; (1.94 ppm mass error) from control plasma;
- FIG. 2B is a graph validating the dicarboxylic structure of VLCDCA 28:4 having a molecular anion of 570.3772 amu (0.53 ppm mass error) by sequential derivatization of 1 carboxylic group with [ 2 H 4 ]taurine and methylation of the second carboxylic group with trimethylsilyl diazomethane with control plasma extracts;
- FIG. 2C is a graph validating the dicarboxylic structure of the stable isotope internal standard [ 2 H 28 ]VLCDCA 26:0 which is sequentially reacted with [ 2 H 4 ]taurine and trimethylsilyl diazomethane to yield an anion of 438.4278 amu which is monitored with 0.46 ppm mass error;
- FIG. 3A is a table of VLCDCA levels in the plasma of different animal species and in different human biofluids
- FIG. 3B is a chart illustrating decreased VLCDCA 28:4 plasma levels in plasma of patients diagnosed with kidney cancer and colorectal cancer;
- FIG. 4 is a table listing the human biofluid levels of VLCDCA 28:6 and assessment of levels in the plasma of other species.
- FIG. 5 is a table illustrating a listing of carboxylic ester prodrugs of dicarboxylic acids and corresponding structures.
- VLCDCAs very-long chain dicarboxylic acids
- VLCDCA 28:4n6 One particular very-long chain dicarboxylic acid (VLCDCA) with 28 carbons and 4 double bonds has potential as a diagnostic marker and as a supplement to provide protection against cancer development.
- VLCDCA 28:4n6 This VLCDCA (hereinafter identified as VLCDCA 28:4n6) has formula (I):
- lipid extracts within human plasma or serum which have monitored decreases in a number of molecules having atomic masses between 444 and 555 amu in patients diagnosed with pancreatic or colorectal cancer are identified as VLCDCAs.
- VLCDCA 28:4 lipid extracts within human plasma or serum which have monitored decreases in a number of molecules having atomic masses between 444 and 555 amu in patients diagnosed with pancreatic or colorectal cancer.
- conversion of VLCFAs to dicarboxylic acids first involve ⁇ -oxidation of the fatty acid by microsomal CYP4F, followed by conversion to an aldehyde via alcohol dehydrogenase, and the final conversion to a VLCDCA by CYP4F or by fatty aldehyde dehydrogenase.
- the present inventive concept provides a characterization of VLCDCAs of up to 36 carbons in length.
- VLCDCAs up to 36 carbons in length may be used as lipid biomarkers of various cancers, such as for example colorectal, ovarian, prostate, and pancreatic cancers.
- the present general inventive concept provides an accurate identification of the VLCDCA biomarker masses between 444 and 555 amu., which have been monitored to decrease in number within lipid extracts of human plasma or serum from patients diagnosed with colorectal cancer and pancreatic cancer.
- these lipid biomarkers are identified as VLCDCAs with 1 to 4 double bonds and 0, 1, or 2 hydroxy substitutions.
- FIGS. 1A and 1B are tables illustrating a listing of VLCDCAs extracted from human blood plasma.
- sequential fatty acid elongation involves elongation of very-long-chain fatty acids—4 (ELOVL4), an enzyme found in moderate levels in brain, spleen, pancreas, kidney, ileum, and lymph nodes, and in high levels in primate retina, thymus, epidermis, and germ cells.
- ELOVL4 very-long-chain fatty acids
- These very-long-chain fatty acids perform structural functions as fatty acid components of sphingomyelins and photophatidylcholines, serve in signal transduction roles, and are potential precursors to dicarboxylic acids.
- FIG. 2A is a graph of VLCDCA 28:4 having a spectrum molecular anion of 445.332 amu (1.94 ppm mass error) prior to sequential derivatization of 1 carboxylic group with [ 2 H 4 ]taurine and methylation of the second carboxylic group with trimethylsilyl diazomethane.
- FIG. 2B is a graph validating a dicarboxylic structure (VLCDCA 28:4) having a molecular anion of 570.3772 amu (0.53 ppm mass error) by sequentially reacting organic extracts of control plasma with [ 2 H 4 ]taurine and trimethylsilyl diazomethane. Referring to FIGS.
- a reaction of a lipid extract of 1000 uL of control plasma and [ 2 H 4 ]taurine and trimethylsilyl diazomethane derivatizes both carboxylic acid groups.
- the molecular anion 445.3323 amu is identified as a VLCDCA with 4 double bonds and no hydroxy substitutions.
- This lipid is properly identified and assigned as dicarboxylic acid 28:4, rather than the previous assignment as a fatty acid with 5 double bonds and 2 hydroxy substitutions (GTA-446).
- a method of validating the dicarboxylic acid 28:4 structure includes derivatization of the two carboxylic groups in VLCFA 28:4 by using [ 2 H 4 ]taurine and trimethylsilyl diazomethane.
- This validation method includes obtaining blood samples collected by venipuncture and then isolating a sample of either serum or ethylenediaminetetraacetic acid (EDTA) plasma from the blood samples.
- the sample of serum and/or the EDTA plasma may, in certain embodiments, be stored in a low temperature environment (e.g. a refrigerator) or frozen to limit degradation of the sample prior to analysis.
- a sample of approximately 100 microliters of serum and/or EDTA plasma is mixed with 1 milliliter (mL) of methanol containing 1 nanomole of [ 2 H 28 ] dicarboxylic acid 16:0, of the type supplied, for example, by CDN Isotopes, 88 Ave. Leacota, PointeClaire, QC, H9R 1H1, to form a sample mixture.
- 1 milliliter of distilled water and 2 milliliters of tert-butyl methylether are added to the sample mixture.
- the sample mixture is then agitated in an organic solvent in order to extract the lipid fraction.
- the sample mixture is shaken at a high speed (e.g., setting 9 of the Fisher Multitube Vortex) for approximately 30 minutes at room temperature.
- the sample mixture is then settled in order to separate an organic upper layer from the remainder of the sample.
- the sample mixture is transferred to a test tube and centrifuged at approximately 3000 times gravity at room temperature for approximately 10 minutes.
- approximately 1 milliliter of the upper organic layer is transferred to a 1.5 milliliter microtube and dried, for example by centrifugal vacuum evaporation, prior to dissolution of the dried upper organic layer portion in a mixture of isopropanol, methanol, and chloroform, at a ratio of 4:2:1, respectively, containing about 15 millimolar (mM) ammonium acetate.
- the present general inventive concept is not limited to a particular type or model of mass spectrometer.
- the input lines to the orbitrap mass spectrometer may be washed using methanol and a mixture of hexane and ethyl acetate, in a ratio of 3:2, respectively, between samples.
- negative ion electrospray ionization the anions of dicarboxylic acid are quantitated, and from the acquired high-resolution dataset, the data may be reduced to provide a listing of VLCDCA, as illustrated in FIG. 1 .
- Validation of two carboxylic groups in VLCFA 28:4 was obtained by sequential derivatization of 1 carboxylic group with [ 2 H 4 ]taurine and methylation of the second carboxylic group with trimethylsilyl diazomethane.
- the validation method includes adding approximately 1 milliliter of dried lipid extracts to 50 ⁇ L of 2-chloro-1-methypyrinium iodide (15.2 mg per 10 milliliters of acetonitrile and 16.4 ⁇ L of trimethylamine). The samples are heated at 30° C. with shaking for 15 minutes, followed by the addition of 50 ⁇ L of [ 2 H 4 ]taurine (5 mg in 900 ⁇ L of distilled water and 100 ⁇ L of acetonitrile).
- the samples are heated at 30° C. with shaking for another 2 hours before being dried by vacuum centrifugation.
- 100 ⁇ L of 2-propanol and 20 ⁇ L of trimethylsilyl diazomethane (2 M in hexane) are added and the samples heated at 30° C. with shaking for 30 minutes.
- 20 ⁇ L of glacial acetic acid are added to consume any remaining trimethylsilyl diazomethane.
- the samples are then dried by vacuum centrifugation.
- the mixture is then subjected to dissolution in a mixture of isopropanol, methanol, and chloroform, in ratios of 4:2:1, respectively, containing approximately 15 mM of ammonium acetate.
- the mixture is analyzed in negative ESI (140,000 resolution) to monitor the anion of the derivatized lipids. This involves the addition of 111.02931 ([ 2 H 4 ]taurine) and 14.01565 (trimethylsilyl diazomethane) amu yielding a product of 571.3845 (446.33960+111.02931+14.01565) and an anion of 570.3772 which is monitored with 0.53 ppm mass error ( FIG. 2B ).
- the lipids first undergo sequential derivatization of 1 carboxylic group with [ 2 H 4 ]taurine and methylation of the second carboxylic group with trimethylsilyl diazomethane.
- the hydroxyl groups are derivatized with [ 2 H 6 ]acetic anhydride.
- the 2 carboxylic acid functions are derivatized as described above.
- the samples are then dried and 75 ⁇ L of pyridine and 75 ⁇ L [ 2 H 6 ]acetic anhydride added.
- the data may be reduced simply as a ratio of a peak area of an endogenous lipid to a peak area of a stable isotope internal standard.
- standard curves may be constructed for absolute quantitation, when analytical standards are available.
- VLCFAs may be quantitated by tandem mass spectrometry (MS 2 ) or various other mass spectrometers, including, but not limited to, unit resolution mass spectrometry with a triple quadrupole instrument.
- MS 2 tandem mass spectrometry
- various conventional chromatographic methods such as liquid chromatography, capillary zone electrophoresis, and supercritical fluid chromatography may be used as alternatives to direct infusion.
- the present general inventive concept is not limited thereto.
- FIG. 3A is a table of VLCDCA levels in the plasma of different animal species and in different human biofluids. These data show that VLCDCA is only present in the blood of higher primates indicating that this lipid represents a late evolutionary development. In humans, VLCDCA is present in a wide diversity of biofluids in addition to blood plasma.
- FIG. 3B is a chart illustrating decreased VLCDCA 28:4 plasma levels in plasma of patients with kidney cancer, colorectal cancer, head and neck cancer, and rheumatoid arthritis.
- the plasma levels of VLCDCA 28:4 are decreased in plasma of patients with colorectal cancer, as compared to plasma levels of VLCDCA 28:4 within a control group.
- the plasma levels of VLCDCA 28:4 are also decreased in plasma of patients with kidney cancer, head and neck cancer, and rheumatoid arthritis.
- VLCDCA 28:4 plasma levels as an indicator of various types of cancer, and the present general inventive concept is not limited to these cancer types.
- plasma levels of VLCDCA 28:4 are biomarkers of chronic and progressive inflammatory diseases like rheumatoid arthritis but not restricted to rheumatoid arthritis.
- these biomarker masses have been detected prior to cancer development.
- these biomarker masses are not restored post-surgery to remove identified cancerous tissues, which suggests that these biomarker masses are not derived from the cancerous tissues and may represent intrinsic chemoprotective factors.
- supplements of these factors including VLCDCAs such as VLCDCA 28:4, may be provided to people who have been identified as having a higher risk of developing certain types of cancers to provide protection against cancer development.
- purified fractions of these identified lipids from human plasma have been observed to possess both anti-inflammatory and anti-proliferative properties.
- the identified lipid biomarker VLCDCA 28:4 is generated by a conversion of VLCFAs. This conversion first involves w-oxidation of the VLCFA 28:4 (VLCFA 28:4n6) by microsomal CYP4F, followed by conversion to an aldehyde via alcohol dehydrogenase, and the final conversion to VLCDCA 28:4n6 by CYP4F or by fatty aldehyde dehydrogenase. While VLCDCAs of up to 26 carbons have been previously reported, the present inventive concept provides a characterization of VLCDCAs of up to 36 carbons in length. However, the present general inventive concept is not limited thereto.
- methods of quantitation of serum or plasma levels of the identified lipid biomarker VLCDCA 28:4 within a subject may be used to monitor these lipids as risk factors for developing a plurality of cancers, including, but not limited to, colorectal, kidney, prostate, and pancreatic cancers.
- VLCFAs may be quantitated by MS2 on various other mass spectrometers including unit resolution mass spectrometry with a triple quadrupole instrument.
- chromatographic methods may also be used as alternatives to direct infusion methods, which may include liquid chromatography, capillary zone, electrophoresis, and supercritical fluid chromatography.
- the present general inventive concept is not limited thereto.
- FIG. 4 is a table illustrating a listing of carboxylic ester prodrugs of dicarboxylic acids and corresponding structures.
- the identified lipid biomarker VLCDCA 28:4 or potential esters of VLCDCA 28:4 may be used in the development of various pharmaceutical analogs or prodrugs of these lipids, which may be used as cancer treatment medication or as cancer chemoprevention medicines.
- mono- and di-esters of the identified lipid biomarker VLCDCA 28:4 may be used in the development of prodrugs.
- the identified lipid biomarker VLCDCA 28:4 according to present general inventive concept may be provided in pharmaceutical compositions including a carrier or in combination with various other agents or drugs.
- the identified lipid biomarker VLCDCA 28:4 according to present general inventive concept may be provided as supplements, nutraceuticals, and/or combined with various other foods.
- the identified lipid biomarker VLCDCA 28:4 according to present general inventive concept may be administered to a subject diagnosed with at least one of a plurality of cancers, including, but not limited to, colorectal, kidney, prostate, and pancreatic cancers, in an amount sufficient to treat, prevent, and/or mitigate the cancer.
- the present general inventive concept provides a method of treating a subject having colorectal cancer.
- the present general inventive concept also provides a chemopreventive agent and a method of treating a subject having low circulating levels of VLCDCAs with the chemopreventive agent.
- the treatment method includes administering to the subject having colorectal cancer or low circulating levels of VLCDCAs a sufficient amount of VLCDCAs to increase the level of VLCDCAs circulating in the blood a compound according to the formula (I), a prodrug of (I), or an analog of (I):
- the present general inventive concept provides a method of treating a subject having pancreatic cancer and as a chemopreventive agent in individuals with low circulating levels of VLCDCAs.
- the treatment method includes administering to the subject having pancreatic cancer or low circulating levels of VLCDCAs a sufficient amount of VLCDCAs to increase the level of VLCDCAs circulating in the blood a compound according to the formula (I), a prodrug of (I), or an analog of (I):
- the present general inventive concept provides a method of treating a subject having prostate cancer and as a chemopreventive agent in individuals with low circulating levels of VLCDCAs.
- the treatment method includes administering to the subject having prostate cancer or low circulating levels of VLCDCAs a sufficient amount of VLCDCAs to increase the level of VLCDCAs circulating in the blood a compound according to the formula (I), a prodrug of (I), or an analog of (I):
- VLCDCAs listed in FIG. 1A
- structural analogs or prodrug esters of these VLCDCAs are also potential therapeutic candidates for increasing the level of VLCDCAs circulating in the blood and treating colorectal cancer.
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CA3039196A CA3039196A1 (en) | 2016-10-03 | 2017-10-02 | Identification and use of very long chain dicarboxylic acids for disease diagnosis, chemoprevention, and treatment |
AU2017339427A AU2017339427A1 (en) | 2016-10-03 | 2017-10-02 | Identification and use of very long chain dicarboxylic acids for disease diagnosis, chemoprevention, and treatment |
CN201780073711.3A CN110325863B (zh) | 2016-10-03 | 2017-10-02 | 极长链二羧酸用于疾病诊断、化学预防和治疗的鉴定和应用 |
JP2019538572A JP2019530883A (ja) | 2016-10-03 | 2017-10-02 | 疾患診断、化学予防、および処置のための超長鎖ジカルボン酸の同定および使用 |
EP17858952.9A EP3519835A4 (en) | 2016-10-03 | 2017-10-02 | IDENTIFICATION AND USE OF VERY LONG-CHAIN DICARBOXYLIC ACIDS FOR THE DIAGNOSIS, CHEMOPREVENTION AND TREATMENT OF DISEASES |
GB1906195.1A GB2569932B (en) | 2016-10-03 | 2017-10-02 | Identification and use of very long chain dicarboxylic acids for disease diagnosis, chemoprevention, and treatment |
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US15/969,940 US11073522B2 (en) | 2016-10-03 | 2018-05-03 | Structural validation of very long chain dicarboxylic acids |
US17/386,092 US20220034895A1 (en) | 2016-10-03 | 2021-07-27 | Method of Determining Disease State Risk |
JP2022131678A JP2022166259A (ja) | 2016-10-03 | 2022-08-22 | 疾患診断、化学予防、および処置のための超長鎖ジカルボン酸の同定および使用 |
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Cited By (2)
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WO2019213480A1 (en) * | 2018-05-03 | 2019-11-07 | Lincoln Memorial University | Structural validation of very long chain dicarboxylic acids |
EP3773647A4 (en) * | 2018-04-13 | 2022-01-26 | Med-Life Discoveries LP | LONG CHAIN DICARBOXYLIC FATTY ACID (LCDFA) PRODUCING MICROBES AND THEIR USES |
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IL121165A0 (en) * | 1997-06-26 | 1997-11-20 | Yissum Res Dev Co | Pharmaceutical compositions containing carboxylic acids and derivatives thereof |
EP1650568A1 (en) * | 2000-07-10 | 2006-04-26 | Esperion Therapeutics Inc. | Fourier transform mass spectrometry for diagnosis of diseases |
ES2295907T3 (es) * | 2004-08-13 | 2008-04-16 | Indivumed Gmbh | Uso de transtiretina como biomarcador para ademona colorrectal; metodo para la deteccion y sistema de ensayo. |
WO2006092689A1 (en) * | 2005-03-03 | 2006-09-08 | Warner-Lambert Company Llc | Assay of sebum and meibum lipid components by mass spectrometry |
SG182169A1 (en) * | 2005-09-12 | 2012-07-30 | Phenomenome Discoveries Inc | Method for the diagnosis of colorectal cancer and ovarian cancer by the measurement of vitamin e-related metabolites |
CA2759011A1 (en) * | 2009-04-17 | 2010-10-21 | The Ohio State University Research Foundation | Antiadhesion agents |
CA2768086A1 (en) * | 2009-07-29 | 2011-02-03 | Phenomenome Discoveries Inc. | Hydroxy fatty acid compounds and uses thereof for disease treatment and diagnosis |
US8728824B2 (en) * | 2011-06-22 | 2014-05-20 | Quest Diagnostics Investments Inc. | Mass spectrometric determination of fatty acids |
US20150008314A1 (en) * | 2012-01-26 | 2015-01-08 | The Cleveland Clinic Foundation | Diagnostic and prognostic biomarkers for cancer |
WO2014068124A1 (en) * | 2012-11-05 | 2014-05-08 | Diagnoplex Sa | Biomarker combinations for colorectal tumors |
WO2015104113A1 (en) * | 2014-01-08 | 2015-07-16 | Nestec S.A. | Biomarkers for epicardial adipose tissue |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3773647A4 (en) * | 2018-04-13 | 2022-01-26 | Med-Life Discoveries LP | LONG CHAIN DICARBOXYLIC FATTY ACID (LCDFA) PRODUCING MICROBES AND THEIR USES |
WO2019213480A1 (en) * | 2018-05-03 | 2019-11-07 | Lincoln Memorial University | Structural validation of very long chain dicarboxylic acids |
GB2587937A (en) * | 2018-05-03 | 2021-04-14 | Lincoln Memorial Univ | Structural validation of very long chain dicarboxylic acids |
JP2021523350A (ja) * | 2018-05-03 | 2021-09-02 | リンカーン メモリアル ユニバーシティー | 超長鎖ジカルボン酸の構造的な検証 |
GB2587937B (en) * | 2018-05-03 | 2023-07-12 | Lincoln Memorial Univ | Structural validation of very long chain dicarboxylic acids |
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GB2569932A (en) | 2019-07-03 |
AU2017339427A1 (en) | 2019-05-23 |
JP2019530883A (ja) | 2019-10-24 |
EP3519835A1 (en) | 2019-08-07 |
CN110325863A (zh) | 2019-10-11 |
JP2022166259A (ja) | 2022-11-01 |
GB2569932B (en) | 2022-11-23 |
GB201906195D0 (en) | 2019-06-19 |
CN110325863B (zh) | 2023-05-09 |
WO2018067434A1 (en) | 2018-04-12 |
CA3039196A1 (en) | 2018-04-12 |
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